• No results found

<p>Novel variants of unknown significance in the <em>PMS2</em> gene identified in patients with hereditary colon cancer</p>

N/A
N/A
Protected

Academic year: 2020

Share "<p>Novel variants of unknown significance in the <em>PMS2</em> gene identified in patients with hereditary colon cancer</p>"

Copied!
7
0
0

Loading.... (view fulltext now)

Full text

(1)

O R I G I N A L R E S E A R C H

Novel variants of unknown signi

cance in the

PMS2

gene identi

ed in patients with hereditary colon

cancer

This article was published in the following Dove Press journal: Cancer Management and Research

Raffaella Liccardo1

Carlo Della Ragione2

Nunzio Mitilini2

Marina De Rosa1

Paola Izzo1

Francesca Duraturo1

1Department of Molecular Medicine and Medical Biotechnologies, School of Medicine, University of Naples“Federico II”, Naples, Italy;2UOC Pathological Anatomy, AORN“A. Cardarelli”, Naples, Italy

Background: Lynch syndrome is associated with genetic variants in mismatch repair

(MMR) genes. Pathogenic variants in theMLH1 and MSH2 genes occur in most families

in which the phenotype is highly penetrant. These testing criteria are likely to miss

indivi-duals with Lynch syndrome due to the less penetrant MMRgenes, such asMSH6, MLH3,

MSH3, and PMS2. So far, several mutations in the PMS2 gene have been described as responsible for the clinical manifestation of Lynch syndrome. Recent data have reported that families with atypical Lynch phenotype were found to have primarily monoallelic mutations

in thePMS2gene.

Methods: We analyzed the PMS2 gene to detect mutations in members of 64 Lynch

syndrome families by direct sequencing.

Results:We report the identification of several genetic variants in patients with LS, of which

three are novel variants. The carriers of these novel variants were also carried of other

variants inPMS2gene and/or in otherMMRgenes.

Conclusion:Therefore, we think that these novelPMS2variants may act in additive manner

to manifestation LS phenotype.

Keywords:Lynch syndrome, PMS2 gene, MMR genes, PMS2 variants, synergist effect of

MMR variants

Introduction

The primary clinical manifestation of Lynch Syndrome is the development of colon cancer at an average age of 45 years; this syndrome is also characterized by an increased risk of developing extra-colonic tumors such as endometrial,

ovarian, stomach, urinary, and biliary tract cancer.1 Families affected by LS

were identified using the Amsterdam Criteria (AC) and Bethesda guidelines

(BG).2,3Lynch syndrome (LS) testing criteria were developed based on families

with cancer histories across multiple generations. LS is associated with genetic

variants in DNA Mismatch Repair (MMR) genes and it is characterized at

somatic level by high instability of microsatellite sequences (MSI).4,5

Pathogenic variants in the MLH1 and MSH2 genes occur in most families in

which the phenotype is highly penetrant.6,7 Pathogenetic variants in the less

penetrant MMR genes, such as MSH6, MLH3, MSH3, and PMS2 were also

shown in LS patients.8–10

The PMS2 gene is located on chromosome 7p22 in a region spanning 16 kb

and is made up of 15 exons and 862 codons.11 The PMS2 protein acts as

Correspondence: Francesca Duraturo Department of Molecular Medicine and Medical Biotechnologies, School of Medicine, University of Naples“Federico II”, Via Pansini, 5, Napoli 80131, Italy Email francesca.duraturo@unina.it

Cancer Management and Research

Dove

press

open access to scientific and medical research

Open Access Full Text Article

Cancer Management and Research downloaded from https://www.dovepress.com/ by 118.70.13.36 on 20-Aug-2020

(2)

a heterodimer together with MLH1 protein forming the

MutLαcomplex that is associated with the MutSα

com-plex, which primarily repairs single-nucleotide

mismatches.12 Its function is redundant with the MLH3

gene product. Mice that have the PMS2 gene deleted develop lymphomas and sarcomas but not gastrointestinal tumors; instead, mice lacking PMS2 and MLH3 develop a non-distinguishable phenotype from MLH1 knock-out

mice.13Finally, it has also shown that the PMS2 gene is

also involved in the apoptotic pathway.14

So far, several mutations in thePMS2gene have been

described as responsible for the clinical manifestation of

Lynch syndrome.15–17 The large rearrangements in the

PMS2gene are rarely described.18,19Recent studies have

demonstrated a reduced penetrance for monoallelic

car-riers of PMS2 mutations compared to the other MMR

genes.20Moreover, very often homozygous and/or biallelic

point mutations in thePMS2gene have been reported to be

responsible for Lynch phenotypes;21,22as it has been also

described thatPMS2mutations together with mutations in

other MMR genes should also be considered in patients

suspected to present a Lynch syndrome with an unusual early-onset of tumors.23

The aim of this study was to analyze thePMS2gene to

detect mutations in members of 64 LS families. We have

identified 21 variants in the PMS2 gene; of which no

variant was of certain pathogenetic significance. Most of

these variants had previously been described in the litera-ture, only three of these are novel, of which two are missense variants that could alter the functionality of the protein.

Materials and methods

Patients and isolation of genomic DNA

Sixty-four LS patients were recruited from several hospi-tals in southern Italy; patients were previously estab-lished to be negative for pathogenetic mutations in other

MMR genes includingMLH1, MSH2, MSH6, andMLH3

and included large rearrangements in PMS2 gene.19

Twenty-three families with classic LS phenotype were selected by AC 2 and 41 families with atypical Lynch phenotype were selected by MSI analysis as suggested

BG1Sixty samples from healthy patients collected from

the Clinical Department of Laboratory Medicine of the

hospital affiliated with Federico II University (Naples,

Italy) were used as negative controls. The experiments

were performed on DNA extracted from peripheral blood lymphocytes. Total genomic DNA was extracted from 4 mL peripheral blood lymphocytes using a BACC2 Nucleon kit (Amersham Pharmacia Biotech, Amersham, UK). The Clinical Department of Laboratory Medicine of

the hospital affiliated to Federico II University (Naples,

Italy) recruited the subjects after receiving authorization

from the local ethics committee “Comitato etico per le

attività Biomediche Carlo Romano”of the University of

Naples, Federico II (protocol no. 120/10). Once the authorization was obtained, the study received ethical

approval, and participants’ informed and written consent

was obtained. The experiments were performed on DNA

and on cDNA extracted from peripheral blood

lymphocytes.

Mutation analysis and in silico analysis

The entire coding region of thePMS2gene was amplified

in 17 fragments, 1 for each exon and 3 overlapping fragments for exon 11, using customized primer sets, available upon request. The polymerase chain reaction

(PCR) products were separated on a 1–2% agarose gel

to check for unspecific amplicons. Subsequently, the PCR

products were sequenced in both the forward and reverse directions using an ABI 3100 Genetic Analyzer (Applied Biosystems).

The Sorting Intolerant From Tolerant (SIFT) (http://

blocks.fhcrc.org/sift/SIFT.html) and Polymorphism

Phenotyping (PolyPhen) (http://genetics.bwh.harvard.

edu/pph/) tools were used for functional impact predic-tion of the novel variants, as described in our previous studies.6

Immunohistochemistry (IHC)

IHC was performed on a Benchmark XT automatized immunostainer (Ventana Medical Biosystems, Tucson, AZ, USA). The antibodies used were anti-MSH6, mouse monoclonal clone 44; anti-MSH2, mouse monoclonal clone G219-1129; anti-MLH1, mouse monoclonal clone M1 (Ventana); and anti-PMS2. The procedure was per-formed as described previously on sections of colon cancer tissues.9

Results

The mutation detection analysis of the PMS2 gene,

per-formed on samples from patients with LS, as described in

the Materials and Methods section, identified 21 genetic

Cancer Management and Research downloaded from https://www.dovepress.com/ by 118.70.13.36 on 20-Aug-2020

(3)

T able 1 V ariants identi fi ed in the PMS2 gene in our study Exon Nucleotide chang e Aminoacid chang e Refer ence P atho g enicity (www .insight-gr oup .org) F requency in her editar y CRC Fr equency in health y samples 15 ’ UTR c.-1 54g>c Thompson et al, 11 2004 ND 12/64 (19%) ND 5 ’ UTR c.-1 95t>c Thompson et al, 11 2004 ND 3/64 (4.7%) ND 5 ’ UTR c.+72c>t This study Lik ely Class 1 12/64 (19%) 4/60 2 c.52A>G p .(Ile17V al) Hendrinks et al, 24 2006 Class 2 1/64 (1.6%) ND c.59G>A p .(Arg20Gln) Nicolaides et al, 25 1994 Class 1 6/64 (9.4%) ND 3 c.250+108a>g Hendrinks et al, 24 2006 ND 7/64 (11%) ND 6 c.705+17>g Thompson et al, 11 2004 ND 10/64 (15.8%) ND 7 c.780C>G p .Ser260= Viel et al, 26 1998 Class 1 Heter ozygous 3/64 (4.7%); Homozigous 13/ 64 (20%) ND 11 c.1454C>A p .(Thr485L ys) W ang et al, 27 1999 Class 1 4/64 (6.3%) ND c.1621G>a p .(Glu540L ys) Viel et al, 26 1998 Class 1 10/64 (15.8%) ND c.1789A>T p .(Thr596Ser) Viel et al, 26 1998 Class 1 1/64 (1.6%) ND c.2007 − 4g>a Hendrinks et al, 24 2006 ND 15/64 (23.4%) ND c.2174+24c>a Hendrinks et al, 24 2006 ND 6/64 (9.4%) ND 13 c.2248G>A p .(Gly749Ser) This study Lik ely Class 3 1/64 (1.6%) 0/60 c.2253T>C p .Phe 751= Viel et al, 26 1998 Class 1 10/64 (15.8%) ND 14 c.2324A>G p .(Asn774Ser) Viel et al, 26 1998 Class 1 14/64 (22.2%) ND c.2340C>T p .Pr o780= Hendrinks et al, 24 2006 Class 1 3/64 (4.7%) ND c.2380C>T p .(Pr o793Ser) This study Lik ely Class 3 2/64 (3.2%) 0/60 15 c.2466T>C p .Leu822= Viel et al, 24 1998 Class 1 10/64 (15.8%) ND c.2570G>C p .(Gly857Ala) Viel et al, 26 1998 Class 1 23/64 (36%) ND Note: NCBI accession number : NM000535. Abbre viations: ND , not done; CRC , colon re ctal cancer .

Cancer Management and Research downloaded from https://www.dovepress.com/ by 118.70.13.36 on 20-Aug-2020

(4)

variants (Table 1). These variants were shown in both

families’ groups (AC and BG respecting), casually. No

variant of certain pathogenetic significance was identified in this study. Most variants had previously been described

in the literature and reported in theMMRvariants database

of Insight Group (https://insight-database.org/variants/), while three were novel variants, of which two were mis-sense variants. The two novel mismis-sense variants were analyzed using a bioinformatic tool that predicted that both these variants were likely pathogenic. These missense

variants were identified in three unrelated LS families

(Table 2). The genetic variant, c.2248G>A, located in

exon 13 of the gene, was identified in a subject who

developed right-side colon carcinoma at the age of 34

years. This variant was also identified in the father of

this proband, who also developed colon cancer at 40 and in a paternal uncle who developed colon cancer at age 45. Thus, the mutation segregates with the disease in this family. Moreover, this variant was not found in the 60 healthy subjects used as negative controls. In silico analy-sis indicated that protein function was likely altered as a result of the mutation. The IHC analysis did not provide

results due to paraffin-embedded tumoral tissue of poor

quality. The father and son of this family were also carriers

of unclassified variants inMSH2genes, a missense variant

in exon 3, the c.573C>T (p.Pro125Ser), already reported in

“Insight Variants Database” (Table 2). The second novel

PMS2 missense variant, the c.2380C>T in exon 14, was

identified in two unrelated LS patients, and it was also not found in the 60 healthy subjects used as negative controls. Thein silico analysis revealed that this variation has also a high probability of altered protein function; the IHC analysis showed normal expression of the PMS2 protein at the somatic level, (Table 2).

Discussion

For many years, the PMS2 gene has been considered

a gene candidate for the development of cancer in Lynch Syndrome. However, to date, its role in the development of cancer in Lynch syndrome is still not well understood. It

has been reported that monoallelic mutations in thePMS2

gene are responsible for the phenotype found in families that do not fully comply with the Amsterdam criteria or

who develop non-LS-related tumors.20 This can be

explained considering that mice lacking PMS2 develop

lymphomas and sarcomas but not gastrointestinal

tumors.12

In this study, all variants identified in the PMS2gene

are unclassified, including also the novel variants.

Bioinformatics studies have shown that two novel mis-sense variants may be detrimental to the functionality of the protein. In particular, c.2248G>A, identified in exon 13

of thePMS2gene, was found to segregate with the disease

in the AC family and all family members’ carrier of this

variant developed colon cancer. Our previous investiga-tions showed that the index case of this family and his

father were also carriers of a missense variant in theMSH2

gene, already described in literature as benign variant. Unfortunately, it was not possible to analyze the other

affected family members because didn’t available. The

MSI analysis performed on tumoral colon tissue of the index case showed a high MSI status (data not shown). Instead, the IHC investigations did not provide reliable

results due to poor quality of the paraffin-embedded

tumor tissue from the index case; therefore, we have not

been able to escape a deficiency of MMR proteins at the

somatic level associated with other causes, such as

hyper-methylation of theMLH1promoter1Thus, we speculated

that likely these two variants identified in this family may

act as low-risk alleles that together determine the defi

-ciency of MMR system, as shown by high MSI status on tumoral DNA of index case. Also the other missense variant identified in this study, the c.2380C>T, in exon

14 of thePMS2gene was found in two unrelated patients

that both showed high MSI status on tumoral colon tissues

(data not shown) but a poor one significant family history

of LS-related cancers. However, the IHC analysis per-formed on colon cancer tissue of both index cases (07/6 and 00/12) showed normal expression of MMR proteins, MLH1, MSH2, MSH6, and PMS2 (Table 2). This last data does not contrast with the result of the MSI rather it

reinforces our hypothesis, first formulated; indeed,

a missense mutation is predicted to alter the functionality of the protein but not its production. Moreover, also these

two patients were carriers of other variants inMMRgene.

In particular, the carrier 07/6 showed in addition to novel missense variant also a high numbers of other variants in

PMS2 gene (Figure 1) and a variant in MLH3 gene

(Table 2). Also, the carrier 00/12 showed two variants in

PMS2 (included the novel variant) and one variant in

MLH3 gene. Previously, literature data showed that the

monoallelic mutations in the PMS2 gene are likely

com-patible with a more attenuated Lynch phenotype or a low-penetrance20and, thus in the case of a classical phenotype,

Cancer Management and Research downloaded from https://www.dovepress.com/ by 118.70.13.36 on 20-Aug-2020

(5)

T able 2 L ynch syndr ome patients carrier of nov el PMS2 variants identi fi ed in this study ID MMR g enes variants Micr osatellite instability Immunohistochemistr y Clinical phenotype F amily histor y 05/ 7 MSH2: ex3c.573C>T (p . Pr o125Ser) PMS2: ex7c.780C>G+/+ [p . Ser260=] ex13c. 2248G>A (p . Gly749Ser) a ex13c. 2253T>C [p .Phe 751=] ex14c. 2324A>G (p . Asn774Ser) MSI-H MSH2: +/+ MSH6: ND MLH1: ND PMS2: ND Right-colon cancer at age 44. Father affected by colon cancer at age 36 and 49 years, PMS2 and MSH2 MUT+; paternal uncle died of colon cancer at age 60, PMS2 MUT+; paternal uncle died of lung cancer at age 60 ye ars and his son affected by thr ee right colon adenoma at age 42. 00/ 12 MLH3: ex1-13c.2 896T>C (p .Ser965Pr o) PMS2: ex14c.2324A>G (p . Asn774Ser) ex14c. 2380C>T(p . Pr o793Ser) a MSI-H MSH2: +/+ MSH6: +/+ MLH1: +/+ PMS2: +/+ Right-colon cancer at age 64. Father affected by colon cancer at age 63; paternal aunt died of br east cancer at age 40; sister died of lung cancer at age 63. 07/ 6 MLH1: IVS1+9C>G+/+; MLH3: ex1-13:c.2 896T>C (p .Ser965Pr o) PMS2: ex2c.59G>A (p . Arg20Gln) ex6c.7 05+17a>g, ex7c.7 80C>G +/+[p . Ser260=] ex12c. 2007 – 7c>t, ex12c. 2007 – 4g>a, ex13c. 2253T>C [p .Phe 751=] ex14c. 2380C>T(p . Pr o793Ser) a ex15c. 2466T>C[p .Leu822=] MSI-H MSH2: +/+ MSH6: +/+ MLH1: +/+ PMS2: +/+ Right-colon cancer at age 59. Par ents who died in old age, not affected by neoplastic disease; tw o maternal aunts died of colon cancer at age 55 and 80, respectiv ely . Note: aNov el variant. Abbre viations: ID , identi fi cation number patient; ND , not done; +/+, homozygous variant; Mut+, carrier mutation; MSI-H, high micr osatellite instability; IHC , immunohistoch emistr y.

Cancer Management and Research downloaded from https://www.dovepress.com/ by 118.70.13.36 on 20-Aug-2020

(6)

a second mutation may also be present in samePMS2gene or in anotherMMRgenes.23Even if, all variants identified in this study seem unlikely to have pathogenic effects on protein function it cannot be ruled out that such variants

represent low-penetrance alleles rather than benign var-iants or polymorphisms. Therefore, it is possible that the synergist effect of these low-risk alleles is causing disease manifestation in our patients.

A

EX2 PMS2 (forward)

A A A A A

A

A

A A

A

A A A

A A A A A

A A A A A A

A A A A A

A A

A A A A

A A A

Y

Y

C

C C

C

C C

60

120

210 220

50 130

220 40

140

30

90

90 150

70 130

C

C C C

C

C

C C C

C C C

C C C

C

C C

C C

C C

C

C

C C C

C G

G G

G G G

G

G G

G

G G G G G

G G G G G G

G

G G G

G

G G G

G

G N G

N N

N

N

N N N

N

N

N N

N N N N N

N R

T

T T

T

T T

T T T

T

T T T T T

T T

T T T

T T T T T T

T T T T T

T T

T

T T T T T

EX2 PMS2 (reverse)

EX6 PMS2 (forward) EX6 PMS2 (reverse)

EX7 PMS2 (forward) EX7 PMS2 (reverse)

EX12 PMS2 (forward) EX12 PMS2 (reverse)

EX13 PMS2 (forward) EX13 PMS2 (reverse)

EX14 PMS2 (forward) EX14 PMS2 (reverse)

EX15 PMS2 (forward) EX15 PMS2 (reverse)

B

C

D

E

F

G

N N

Figure 1DNA sequencing electropherograms of the PMS2 exon 2 (A), exon 6 (B), exon 7 (C), exon 12 (D), exon 13 (E), exon 14 (F), and exon 15 (G) for the 07/6 patient

sample. Arrows indicate the homozygous variant in the exon 7 (C), and the heterozygous variants in the exon 2 (A), the exon 6 (B), the exon 12 (D), the exon 13 (E), the

exon 14 (F), and the exon 15 (G). Each variant is shown in the forward (left) and reverse (right) DNA sequencing analysis.

Cancer Management and Research downloaded from https://www.dovepress.com/ by 118.70.13.36 on 20-Aug-2020

(7)

Disclosure

The authors report no conflicts of interest in this work.

References

1. Duraturo F, Liccardo R, De Rosa M, Izzo P. Genetics, diagnosis and treatment of Lynch syndrome: old lessons and current challenges (Review).Oncol Letters.2019;17(3):3048–3054.

2. Vasen HFA, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syn-drome) proposed by the International Collaborative group on HNPCC.Gastroenterology.1999;116:1453–1456.

3. Boland CR, Thibodeau SN, Hamilton SR, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer.

Cancer Res.1998;58:5248–5257.

4. Duraturo F, Izzo P. Detection analysis of microsatellite instability status for the diagnosis and therapy of Lynch syndrome-related cancers.Biochim Clin.2018;42(2):152–154.

5. Rasmussen LJ, Heinen CD, Royer-Pokora B, et al. Pathological assessment of mismatch repair gene variants in Lynch syndrome: past, present, and future. Hum Mutat. 2012;33(12):1617–1625. doi:10.1002/humu.22168

6. Duraturo F, Liccardo R, Cavallo A, De Rosa M, Rossi GB, Izzo P. Multivariate analysis as a method for evaluating the pathogenicity of novel genetic MLH1 variants in patients with colorectal cancer and microsatellite instability. Int J Mol Med. 2015;36:511–517. doi:10.3892/ijmm.2015.2255

7. Liccardo R, De Rosa M, Rossi GB, Rigler G, Izzo P, Duraturo F. Characterization of novel, large duplications in the MSH2 gene of three unrelated Lynch syndrome patients. Cancer Genet.

2018;221:19–24. doi:10.1016/j.cancergen.2017.11.008

8. Duraturo F, Liccardo R, Cavallo A, De Rosa M, Grosso M, Izzo P. Association of low-risk MSH3 and MSH2 variant alleles with Lynch syndrome: probability of synergistic effects. Int J Cancer.

2011;129:1643–1650. doi:10.1002/ijc.25824

9. Liccardo R, De Rosa M, Rossi GB, Carlomagno N, Izzo P, Duraturo F. Incomplete segregation of MSH6 frameshift variants with phenotype of Lynch syndrome. Int J Mol Sci. 2017;18(5). doi:10.3390/ijms18050999

10. Duraturo F, Liccardo R, Izzo P. Coexistence of MLH3 germline variants in colon cancer patients belonging to families with Lynch syndrome-associated brain tumors.J Neurooncol.2016;129:577–578. doi:10.1007/s11060-016-2203-0

11. Thompson E, Meldrum CJ, Crooks R, et al. Hereditary non-polyposis colorectal cancer and the role of hPMS2 and hEXO1 mutations.Clin Genet.2004;65(3):215–225.

12. Hegan DC, Narayanan L, Jirik FR, Edelmann W, Liskay RM, Glazer PM. Differing patterns of genetic instability in mice deficient in the mismatch repair genes Pms2, Mlh1, Msh2, Msh3 and Msh6.

Carcinogenesis.2006;27(12):2402–2408. doi:10.1093/carcin/bgl079

13. Chen PC, Dudley S, Hagen W, et al. Contributions by MutL homo-logues Mlh3 and Pms2 to DNA mismatch repair and tumor suppres-sion in the mouse.Cancer Res.2005;65(19):8662–8670. doi:10.1158/ 0008-5472.CAN-05-0742

14. Marinovic-Terzic I, Yoshioka-Yamashita A, Shimodaira H, et al. Apoptotic function of human PMS2 compromised by the nonsynon-ymous single-nucleotide polymorphic variant R20Q.Proc Natl Acad Sci U S A.2008;105(37):13993–13998. doi:10.1073/pnas.0806435105 15. Haraldsdottir S, Rafnar T, Frankel WL, et al. Comprehensive

population-wide analysis of Lynch syndrome in Iceland reveals foun-der mutations in MSH6 and PMS2. Nat Commun. 2017;8:14755. doi:10.1038/ncomms14755

16. Carethers JM, Stoffel EM. Lynch syndrome and Lynch syndrome mimics: the growing complex landscape of hereditary colon cancer. World J Gastroenterol.2015;21(31):9253–9261. doi:10.3748/wjg.v21.i31.9253 17. van der Klift HM, Mensenkamp AR, Drost M, et al. Comprehensive mutation analysis of PMS2 in a large cohort of probands suspected of Lynch syndrome or Constitutional Mismatch Repair Deficiency Syndrome. Hum Mutat. 2016;37(11):1162–1179. doi:10.1002/ humu.23052

18. van der Klift H, Wijnen J, Wagner A, et al. Molecular characteriza-tion of the spectrum of genomic delecharacteriza-tions in the mismatch repair genes MSH2, MLH1, MSH6, and PMS2 responsible for hereditary nonpolyposis colorectal cancer (HNPCC). Genes Chromosomes Cancer.2005;44(2):123–138. doi:10.1002/gcc.20219

19. Lo Monte AI, Cudia B, Liccardo R, Izzo P, Duraturo F. Involvement of large rearrangements in MSH6 and PMS2 genes in southern Italian patients with Lynch syndrome.EurJ Oncol.2018;23(1):47–51. 20. Blount J, Prakash A. The changing landscape of Lynch syndrome due to

PMS2 mutations.Clin Genet.2018;94(1):61–69. doi:10.1111/cge.13205 21. Herkert JC, Niessen RC, Olderode-Berends MJ, et al. Paediatric intestinal cancer and polyposis due to bi-allelic PMS2 mutations: case series, review and follow-up guidelines.Eur J Cancer.2011;47(7):965–982. Epub 2011 Mar 4. Review. doi:10.1016/j.ejca.2011.01.013

22. Stark Z, Campbell LJ, Mitchell C, et al. Clinical problem-solving. Spot diagnosis. N Engl J Med. 2014;370(23):2229–2236. doi:10.1056/NEJMcps1302661

23. Bougeard G, Olivier-Faivre L, Baert-Desurmont S, et al. Diversity of the clinical presentation of the MMR gene biallelic mutations.Fam Cancer.2014;13(1):131–135. doi:10.1007/s10689-013-9676-1 24. Hendriks YM, Jagmohan-Changur S, van der Klift HM, et al.

Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome). Gastroenterology.

2006;130(2):312–322

25. Nicolaides NC, Papadopoulos N, Liu B, et al. Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature.

1994;371(6492):75–80

26. Viel A, Novella E, Genuardi M, et al. Lack of PMS2 gene-truncating mutations in patients with hereditary colorectal cancer.Int J Oncol.

1998;13(3):565–569

27. Wang Q, Lasset C, Desseigne F, et al. Prevalence of germline muta-tions of hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in 75 French kindreds with nonpolyposis colorectal cancer.Hum Genet.

1999;105(1-2):79–85

Cancer Management and Research

Dove

press

Publish your work in this journal

Cancer Management and Research is an international, peer-reviewed open access journal focusing on cancer research and the optimal use of preventative and integrated treatment interventions to achieve improved outcomes, enhanced survival and quality of life for the cancer patient.

The manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. Visit http://www.dovepress.com/testimonials.php to read real quotes from published authors.

Submit your manuscript here:https://www.dovepress.com/cancer-management-and-research-journal

Cancer Management and Research downloaded from https://www.dovepress.com/ by 118.70.13.36 on 20-Aug-2020

Figure

Figure 1 DNA sequencing electropherograms of the PMS2 exon 2 (exon 14 (sample. Arrows indicate the homozygous variant in the exon 7 (A), exon 6 (B), exon 7 (C), exon 12 (D), exon 13 (E), exon 14 (F), and exon 15 (G) for the 07/6 patientC), and the heterozy

References

Related documents

Sub-grid-scale models parameterise objects in a cell both by the flow resistance and by their shape and size.Yu and Lane (2006) The height-density function is used to displace

With the help of regress and correlation analysis there were further researched the relationships among this chosen indicator of company performance reciprocally with all

Regarding disease outbreaks, a BSE discovery in the United States significantly influences the beef wholesale-to-retail margin; the effect is much higher than any of the other

If natives and immigrants are sufficiently substitutable within various skill groups, then small immigrant wage effects might simply result from small immigrant labor- supply

We have reviewed the condensed interim consolidated financial statements, comprising the consolidated statement of income (Konzern-Gewinn- und Verlustrechnung), con-

A recent meta-analysis of [ 11 C]DASB PET imaging studies have shown that PD patients have a reduction of serotonergic terminals in the raphe nuclei, thalamus,

Likewise, Transmission Voltage customers receive a significant discount on energy charges during summer peak periods, although in this case the discount is driven entirely by

Desphpande, Farley and Webster (1993, in Paulin et al. 2000) indicate that a relation- ship manager is required to have in-depth knowledge of their client’s business and needs.